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Hypertension and Genetic Variation in Endothelial-Specific Genes

Larsson, Erik; Wahlstrand, Bjorn; Hedblad, Bo LU ; Hedner, Thomas; Kjeldsen, Sverre E.; Melander, Olle LU and Lindahl, Per (2013) In PLoS ONE 8(4).
Abstract
Genome-wide association (GWA) studies usually detect common genetic variants with low-to-medium effect sizes. Many contributing variants are not revealed, since they fail to reach significance after strong correction for multiple comparisons. The WTCCC study for hypertension, for example, failed to identify genome-wide significant associations. We hypothesized that genetic variation in genes expressed specifically in the endothelium may be important for hypertension development. Results from the WTCCC study were combined with previously published gene expression data from mice to specifically investigate SNPs located within endothelial-specific genes, bypassing the requirement for genome-wide significance. Six SNPs from the WTCCC study... (More)
Genome-wide association (GWA) studies usually detect common genetic variants with low-to-medium effect sizes. Many contributing variants are not revealed, since they fail to reach significance after strong correction for multiple comparisons. The WTCCC study for hypertension, for example, failed to identify genome-wide significant associations. We hypothesized that genetic variation in genes expressed specifically in the endothelium may be important for hypertension development. Results from the WTCCC study were combined with previously published gene expression data from mice to specifically investigate SNPs located within endothelial-specific genes, bypassing the requirement for genome-wide significance. Six SNPs from the WTCCC study were selected for independent replication in 5205 hypertensive patients and 5320 population-based controls, and successively in a cohort of 16537 individuals. A common variant (rs10860812) in the DRAM (damage-regulated autophagy modulator) locus showed association with hypertension (P = 0.008) in the replication study. The minor allele (A) had a protective effect (OR = 0.93; 95% CI 0.88-0.98 per A-allele), which replicates the association in the WTCCC GWA study. However, a second follow-up, in the larger cohort, failed to reveal an association with blood pressure. We further tested the endothelial-specific genes for co-localization with a panel of newly discovered SNPs from large meta-GWAS on hypertension or blood pressure. There was no significant overlap between those genes and hypertension or blood pressure loci. The result does not support the hypothesis that genetic variation in genes expressed in endothelium plays an important role for hypertension development. Moreover, the discordant association of rs10860812 with blood pressure in the case control study versus the larger Malmo "Preventive Project-study highlights the importance of rigorous replication in multiple large independent studies. (Less)
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type
Contribution to journal
publication status
published
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in
PLoS ONE
volume
8
issue
4
publisher
Public Library of Science
external identifiers
  • wos:000321662800021
  • scopus:84876946170
ISSN
1932-6203
DOI
10.1371/journal.pone.0062035
language
English
LU publication?
yes
id
e25c660c-9ef8-4351-a4c6-68d2c45b0b53 (old id 3979278)
date added to LUP
2013-09-02 07:31:38
date last changed
2019-10-20 04:10:29
@article{e25c660c-9ef8-4351-a4c6-68d2c45b0b53,
  abstract     = {Genome-wide association (GWA) studies usually detect common genetic variants with low-to-medium effect sizes. Many contributing variants are not revealed, since they fail to reach significance after strong correction for multiple comparisons. The WTCCC study for hypertension, for example, failed to identify genome-wide significant associations. We hypothesized that genetic variation in genes expressed specifically in the endothelium may be important for hypertension development. Results from the WTCCC study were combined with previously published gene expression data from mice to specifically investigate SNPs located within endothelial-specific genes, bypassing the requirement for genome-wide significance. Six SNPs from the WTCCC study were selected for independent replication in 5205 hypertensive patients and 5320 population-based controls, and successively in a cohort of 16537 individuals. A common variant (rs10860812) in the DRAM (damage-regulated autophagy modulator) locus showed association with hypertension (P = 0.008) in the replication study. The minor allele (A) had a protective effect (OR = 0.93; 95% CI 0.88-0.98 per A-allele), which replicates the association in the WTCCC GWA study. However, a second follow-up, in the larger cohort, failed to reveal an association with blood pressure. We further tested the endothelial-specific genes for co-localization with a panel of newly discovered SNPs from large meta-GWAS on hypertension or blood pressure. There was no significant overlap between those genes and hypertension or blood pressure loci. The result does not support the hypothesis that genetic variation in genes expressed in endothelium plays an important role for hypertension development. Moreover, the discordant association of rs10860812 with blood pressure in the case control study versus the larger Malmo "Preventive Project-study highlights the importance of rigorous replication in multiple large independent studies.},
  articleno    = {e62035},
  author       = {Larsson, Erik and Wahlstrand, Bjorn and Hedblad, Bo and Hedner, Thomas and Kjeldsen, Sverre E. and Melander, Olle and Lindahl, Per},
  issn         = {1932-6203},
  language     = {eng},
  number       = {4},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Hypertension and Genetic Variation in Endothelial-Specific Genes},
  url          = {http://dx.doi.org/10.1371/journal.pone.0062035},
  volume       = {8},
  year         = {2013},
}